Efficient discrimination between innocuous and pathogenic antigens forms the basis of effective immune function. Appropriate restraint of immune responsiveness is particularly important within the unique environment of the liver, since intrahepatic cells are continuously exposed to foreign antigens from the gut that is introduced via the portal circulation. In general, the liver is constitutively predisposed to tolerant responses. Allogeneic liver transplants are often accepted by patients with minimal requirements for immunosuppressive medications, and oral tolerance to dietary antigens can be abrogated by diversion of blood from the portal vein to the systemic circulation. In addition, chronic and persistent infection of the liver with pathogens such as Plasmodium and hepatitis viruses is a common and significant source of human morbidity and mortality. The ability to manipulate hepatic immune responses would likely find broad clinical applicability;however, development of such strategies will require a better understanding of the mechanisms underlying the balance between immune responsiveness and immune tolerance within the liver. To that end, this proposal focuses on the role of hepatic B cells in the regulation of immune responses in the liver. In mice, hepatic B cells express the immunomodulatory cytokine, IL-10, in response to infection with a parasitic nematode that undergoes enterohepatic migration during its natural life cycle. When transferred into mice lacking endogenous IL-10, these B cells control the extensive hepatic inflammation that otherwise develops in the recipients. We hypothesize that helminth-activated B cells down-regulate inflammation in the liver by adopting an IL-10- dependent regulatory phenotype. We intend to test this hypothesis by first establishing whether hepatic B cells represent a traditional subset(s) of B cells or comprise a unique population within the liver. We will then determine whether hepatic B cells undergo enterohepatic circulation and if antigen specificity is required for exercise of their regulatory effects. We also will examine whether IL-10 is required for generation of the regulatory phenotype and/or the function of committed regulatory cells. Together, these studies will explore the requirements for development of a regulatory lifestyle in hepatic B cells and how IL-10 shapes this phenotype. Moreover, the experiments will refine our understanding of how immune responses are controlled in the liver. PUBLIC HEALTH RELEVANCE: Immune responses must be regulated to prevent excessive inflammation and subsequent tissue injury. Our knowledge of the mechanisms involved in controlling inflammation is incomplete, but it is clear that a balanced immune response is necessary to maintain health. Our studies likely will generate insight into diseases and conditions that are characterized by inappropriate inflammation and provide clues as to how we may manipulate the immune system to alleviate unwanted inflammation.